Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets

Tengdelius, Mattias; Kardeby, Caroline; Fälker, Knut; Griffith, May; Påhlsson, Peter; Konradsson, Peter; Grenegård, Magnus

doi:10.1002/mabi.201600257

Cited by 15 publications

(17 citation statements)

References 34 publications

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“…7,8,12 For these reasons, we synthesized highly sulfated and unbranched glycopolymers of different average chain lengths with fucoidanmimetic properties and compared these with natural fucoidan from F vesiculosus. 6,13,14 We show that, unexpectedly, these fucoidanlike constructs induce human platelet activation predominantly via PEAR1, facilitated by GPIba. In contrast, in mouse platelets, the synthetic compounds induce platelet activation via CLEC-2, again facilitated by GPIba.…”

Section: Introductionmentioning

confidence: 76%

“…Sulfated a-L-fucoside-pendant glycopolymers C329 (n 5 329 average monomeric units) and C13 (n 5 13 average monomeric units), as well as biotinylated glycopolymers (average monomeric units n 5 27), were synthesized as described. 6,14 The sulfated glycopolymers are described in more detail in supplemental Materials and methods and supplemental Table 1. Fucoidan from F vesiculosus $95% (#F8190) and dextran sulfate (#D8906) were purchased from Sigma-Aldrich.…”

Section: Chemicals and Antibodiesmentioning

confidence: 99%

“…Platelets were isolated using 2-step centrifugation and resuspended in Krebs-Ringer glucose buffer with 0.05 U/mL apyrase and 1 mM CaCl 2 , as described. 6…”

Section: Human Platelet Preparationmentioning

confidence: 99%

“…Reactions were stopped using lysis buffer. 6,21 Immunoprecipitation was performed according to the manufacturer's instructions using a Pierce Classic IP Kit (#26146; Thermo Fisher Scientific) in the presence of protease and phosphatase inhibitor cocktails. The level of chemiluminescence and fluorescence was registered using an Odyssey Fc imaging system (LI-COR).…”

Section: Western Blottingmentioning

confidence: 99%

“…5 The conflicting observations are explained by varying chain length, branching, and degree of sulfation. [5][6][7][8] The activation of platelets by sulfated polysaccharides of different monosaccharide backbones has been investigated. Manne et al reported that fucoidan from Fucus vesiculosus activates human and mouse platelets through C-type lectin-like receptor 2 (CLEC-2), 9 whereas a later study showed that higher concentrations also activate GPVI in mouse platelets.…”

Section: Introductionmentioning

confidence: 99%

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Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

et al. 2019

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Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)–dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)–like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

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Section: Introductionmentioning

confidence: 76%

Section: Chemicals and Antibodiesmentioning

confidence: 99%

“…Platelets were isolated using 2-step centrifugation and resuspended in Krebs-Ringer glucose buffer with 0.05 U/mL apyrase and 1 mM CaCl 2 , as described. 6…”

Section: Human Platelet Preparationmentioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

et al. 2019

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Polymer‐Based Drug‐Free Therapeutics for Anticancer, Anti‐Inflammatory, and Antibacterial Treatment

Tavares

Pechar

Chytil

et al. 2021

Macromolecular Bioscience

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This paper summarizes the area of biomedicinal polymers, which serve as nanomedicines even though they do not contain any anticancer or antiinflammatory drugs. These polymer nanomedicines with unique design are in the literature highlighted as a novel class of therapeutics called “drug‐free macromolecular therapeutics.” Their therapeutic efficacy is based on the tailored multiple presentations of biologically active vectors, i.e., peptides, oligopeptides, or oligosaccharides. Thus, they enable, for example, to directly induce the apoptosis of malignant cells by the crosslinking of surface slowly internalizing receptors, or to deplete the efficacy of tumor‐associated proteins. The precise biorecognition of natural binding motifs by multiple vectors on the polymer construct remains the crucial part in the designing of these drug‐free nanomedicines. Here, the rationales, designs, synthetic approaches, and therapeutic potential of drug‐free macromolecular therapeutics consisting of various active vectors are described in detail. Recent developments and achievements for namely B‐cell lymphoma treatment, Gal‐3‐positive tumors, inflammative liver injury, and bacterial treatment are reviewed and highlighted. Finally, a possible future prospect within this highly exciting new field of nanomedicine research is presented.

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Controlling pre-osteoblastic cell adhesion and spreading on glycopolymer brushes of variable film thickness

Hadjicharalambous

Flouraki

Narain

et al. 2018

J Mater Sci: Mater Med

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Controlling the cell behavior on biocompatible polymer surfaces is critical for the development of suitable medical implant coatings as well as in anti-adhesive applications. Synthetic glycopolymer brushes, based on sugar methacrylate monomers have been reported as robust surfaces to resist protein adsorption and cell adhesion. In this study, poly(D-gluconamidoethyl methacrylate) (PGAMA) brushes of various chain lengths were synthesized directly from initiator functionalized glass substrates using surface-initiated atom transfer radical polymerization. The glycopolymer film thicknesses were determined by ellipsometry, whereas the wettability and the morphology of the surfaces were characterized by static water contact angle measurements and atomic force microscopy, respectively. Stable, grafted films with thicknesses in the dry state between 4 and 20 nm and of low roughness (~1 nm) were obtained by varying the polymerization time. Cell experiments with MC3T3-E1 pre-osteoblasts cultured on the PGAMA brushes were performed to examine the effect of film thickness on the cell morphology, cytoskeleton organization and growth. The results revealed good cell spreading and proliferation on PGAMA layers of low film thickness, whereas cell adhesion was prevented on polymer films with thickness higher than ~10 nm, indicating their potential use in medical implants and anti-adhesive surfaces, respectively.

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Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets

Cited by 15 publications

References 34 publications

Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

Polymer‐Based Drug‐Free Therapeutics for Anticancer, Anti‐Inflammatory, and Antibacterial Treatment

Controlling pre-osteoblastic cell adhesion and spreading on glycopolymer brushes of variable film thickness

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